Project Summary This research program is aimed at identifying new pathogenetic mechanisms in Diffuse Large B-Cell Lymphoma (DLBCL), the most common human lymphoma, as a mean to discover new targets for therapeutic intervention. DLBCL is a heterogeneous malignancy comprising genetically and clinically distinct phenotypes, which are derived from the malignant transformation of germinal center (GC) B cells at different stages of differentiation. Recent analysis of the DLBCL genome has identified a multitude of altered genes, most of which with unknown roles in normal GC physiology and lymphomagenesis. Thus, our program will address these issues by two main complementary approaches. First, we will use novel technologies allowing the analysis of signaling pathways and gene expression on a single cell basis from purified GC B cell subpopulations, as a mean to comprehensively identify the programs that are involved in GC development and potentially altered in DLBCL. Second, we will investigate the function and regulation of two GC ?master regulators?, the activity of which is deregulated in DLBCL via mutational mechanisms as well as via alterations in ?upstream? signaling pathways. The overall program is based on our long-standing experience in studying the biology of the GC reaction in relationship to the genetic mechanisms leading to its malignant transformation. We expect that the results of the above studies will identify new targets for therapy, which will be eventually tested pre-clinically in our portfolio of genetically defined mouse models of DLBCL.